rs780431445

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004484.4(GPC3):c.485A>T(p.Asn162Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,604 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.754

Variant links:

Genes affected

GPC3 (HGNC:4451): (glypican 3) Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

GPC3 links:

GPC3 (HGNC:):

GPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPC3	NM_004484.4 linkuse as main transcript	c.485A>T	p.Asn162Ile	missense_variant	3/8	ENST00000370818.8	NP_004475.1	P51654-1Q53H15I6QTG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8 linkuse as main transcript	c.485A>T	p.Asn162Ile	missense_variant	3/8	1	NM_004484.4	ENSP00000359854.3		P51654-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111503

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33703

show subpopulations

Gnomad AFR

AF:

0.0000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097101

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362465

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111503

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33703

show subpopulations

Gnomad4 AFR

AF:

0.0000653

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wilms tumor 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with GPC3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 162 of the GPC3 protein (p.Asn162Ile). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;.;.

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.1

L;L;.

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.9

D;D;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.010

D;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.95

P;.;.

Vest4

0.60

MutPred

0.76

Gain of catalytic residue at V163 (P = 0.0806);Gain of catalytic residue at V163 (P = 0.0806);.;

MVP

0.64

MPC

0.70

ClinPred

0.84

GERP RS

4.3

Varity_R

0.43

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over